Objective: Advanced glycation end products (AGEs) are generated by glucose in diabetes. Flow-mediated remodeling of resistance arteries (RA) is essential for revascularization in ischemic diseases, but this is impaired in diabetes. We hypothesized that breaking AGE crosslinks could improve flow-dependent remodeling in mesenteric RA in Zucker Diabetic Fatty (ZDF) rats. Research Design and Methods: The animals were anesthetized (Isoflurane, 2.5%) and mesenteric resistance arteries were exposed to high (HF) or normal blood flow (NF) after alternate arterial ligation in vivo and were compared to age-matched lean Zucker (LZ) rats. All animals were treated with buprenorphine (Temgesic®; 0.1 mg/kg, s.c.) before and after surgery. Half of the rats were simultaneously treated by i.p. injection with ALT-711 (3 mg/kg per day). Results: In LZ rats, HF artery diameter was larger than for NF vessels, but this was not the case in ZDF rats. Furthermore, endothelium-mediated dilation in ZDF rats, which was lower than in LZ rats, was further decreased in HF arteries. Treatment of rats with the AGE-breaker ALT-711 reversed the diabetes-induced impairment of HF-dependent remodeling, as shown by an increased arterial diameter. Breaking AGE crosslinks also improved cross-sectional compliance and endothelium-dependent relaxation in mesenteric RA. Additionally, contribution of the major endothelium-derived relaxing factor, nitric oxide, increased in acetylcholine-induced relaxation in NF and HF arteries in ZDF rats treated with ALT-711. Accumulation of AGEs and the receptor for AGE expression was reduced by ALT-711 in arteries in ZDF rats. Finally, ALT-711 increased eNOS protein expression in both HF and NF arteries. Conclusions: AGE crosslinks oppose outward remodeling of RA in response to chronic increases in blood flow. Breaking AGE crosslinks provides a therapeutic potential for overcoming the microvascular complications of ischemic diseases in long-term diabetes.